Specific physiological features of inorganic selenium compounds regarding metabolism : in vivo and in vitro investigations with type II diabetic dbdb mice and healthy rats
At present a controversial discussion regarding benefits and risks of selenium (Se) supplements on insulin resistant diabetes and obesity is in progress.The aim of the present studies consequently was to examine molecular coherences and mechanisms behind both aspects of the effects of Se on metabolic processes in different rodent species.
Two animal trials of the present studies focussed on the examination of antidiabetic effects of high supranutritional selenate doses in dbdb mice. Two further animal trials of the present studies with healthy growing rats investigated undesirable effects of Se on the development of insulin resistant diabetes and obesity.
The main results of the studies were:
The oral application of high supranutritional selenate doses also clearly produced antidiabetic effects in type II diabetic dbdb mice with insulin resistance.
In contrast selenite application was inefficient for diabetes therapy in dbdb mice.
In the present work novel findings on the particular molecular mechanism behind the antidiabetic effects of selenate could be pointed out from the fact that selenate treatment effected a distinct amelioration of insulin resistance, followed by changes in the expression and activity of glycolytic and gluconeogenic key enzymes.
Prior studies with type I diabetic animals have linked an increased phosphorylation of downstream proteins in the insulin signalling pathway (beta subunit of the insulin receptor, MAPK, ribosomal S6 kinase) to the antidiabetic virtues of selenate. In the present work it could demonstrated that an increased phosphorylation of insulin signalling proteins and therefore antidiabetic virtues of selenate are based on the inhibition of protein tyrosine phosphatases (PTPs) rather than representing a direct influence of selenate on protein phosphorylation.
In this context another original finding of the present work was that selenate s antidiabetic properties are keenly linked to mammalian Se metabolism. The results of an in vitro inhibition test for PTPs showed that PTP inhibition of orally applied selenate (Se +VI) derives from its intermediary reduction to the thiol-reactive selenite oxidation state +IV, acting as the actual PTP inhibitor. On this account it could be concluded that selenate feeding can be matched by the in vitro use of selenite.
In the rat trials a number of candidate genes, which may mediate undesirable effects of Se on insulin resistant diabetes and obesity, could be evaluated by means of a microarray screening.
In this screening the insulin antagonistic protein tyrosine phosphatase 1B (PTP1B) thereby represented one of the promising genes.
The detailed study of PTP1B regulation revealed that the enzyme was up-regulated by both an optimization of GPx1 activity and by dietary Se supply. Thus dispensable Se supplementation led to a dose-dependent increase in PTP1B activity. The results of the present rat studies therefore could point out for the first time a plausible physiological mechanism by which a permanent surplus of Se can promote the development of insulin resistant diabetes and obesity.
In conclusion the present studies could contribute to a considerably better understanding of the molecular mechanisms by which high supranutritional selenate doses attain antidiabetic effects concerning insulin resistant type II diabetes. The safety of high supranutritional selenate doses, as required for antidiabetic effects, however has so far only been tested in tissue cultures and in animal models, and it is still questionable if selenate application in therapeutical and thus non-physiological doses can be relevant for diabetes treatment in humans.
Secondly the present studies with growing rats could find new aspects how the permanent use of Se supplements, moderately beyond the recommended amounts, may promote the development of insulin resistant diabetes and obesity. In conclusion these results demonstrate the need for future investigations focussing on the influence of Se in metabolic processes. Those investigations should also consider interactions of Se with other antioxidants, with secondary plant substances, as well as the particular nutrition (carbohydrates, sugars, fat, fiber) in order to obtain a better risk assessment. Since the permanent uptake of Se supplements seems to involve risks strict compliance with the current recommendations in human and animal nutrition should be ensured.
Verknüpfung zu Publikationen oder weiteren Datensätzen
